The immune system is alerted to the presence of foreign infectious agents by the presentation of complexes on the surface of the infected cell. The complexes are composed of antigens derived from the pathogen and proteins of the Major Histocompatability Complex (MHC). Two separate pathways, MHC I and MHC II, drive cellular and humoral immune responses, respectively. In general, MHC I-presented antigens are derived from cytoplasmic proteins. However in antigen presenting cells (APC), the MHC I-presented antigens are derived from an alternate pathway through a lysosomal compartment (Morrison et al. J. Exp. Med 163:903-21, 1986; Pfeifer et al. Nature 361:359-62, 1993.) MHC II antigens are generally derived from pinocytotic or phagocytic mechanisms (Morrison et al. J. Exp. Med 163:903-21, 1986).
Of the many pathogenic bacteria capable of mediating disease in humans and animals, intracellular pathogens present unique challenges in attempting to understand bacteria/host cell interactions. Intracellular pathogens are divided into two groups: those that reside within a phagolysosomal compartment (Salmonella sp, Mycobacterium tuberculosis, etc.) and those which reside within the cytoplasm (Listeria monocytogenes, Shigella sp, etc.). Intracellular pathogens adapt to their host cell environment by the selective secretion of proteins designed to alter the normal structural and metabolic machinery of the host cell, thus promoting bacterial survival and avoidance of host immune surveillance. Both phagolysosomal and cytoplasmic intracellular pathogens secrete proteins known to mediate their effects specifically within the host cell cytoplasm (Cornelis and Wolf-Watz, Mol. Microbiol. 23:861-7, 1997; Collazo and Galan, Mol. Microbiol. 24:747-56, 1997; Fu and Galan, Mol. Microbiol. 27:359-68, 1998). Because cytoplasmic localization of the bacterial protein also infers access to the degradative machinery of the host cell proteosome, these proteins were named Class I Accessible Proteins (CAPs).
Vaccination with Salmonella results in the production of a strong cellular and humoral response against the bacteria itself (Sztein et al., J Immunol 155:3987-93, 1995). However, the heterologous-antigen specific immune response is variable and depends on several factors, including the nature of the antigen itself, the type of cell and tissue in which the antigen is expressed, the level of expressi n, and whether the antigen is presented and processed by the class I or class II MHC pathways. Results using either the SIV capsid antigen or the malaria circumspor zoite antigen, demonstrate that antigen-specific cytotoxic T lymphocyte (CTL) responses are induced when the antigen is expressed in Salmonella (Flynn et al., Mol. Microbiol. 4:2111-8, 1990; Sadoff et al., Science, 240:336-8, 1988; Valentine et al., Vaccine. 14:138-46, 1996). Other antigens have failed to elicit a CTL response even in similar expression systems (Tite et al., Immunology 70(4):540-6 1990).
A plasmid containing a gene for a foreign antigen expressed from a eukaryotic promoter resulted in a strong cell-mediated response against the foreign antigen (Darji et al., Cell 91(6):765-75 1997); Schodel and Curtiss, Dev. Biol Stand 84:245-53, 1995).
A significant advance in the area of cancer vaccination has been the identification of tumor-specific epitopes. In general, cancer vaccines attempt to elicit an immune response to tumors by directing tumor-specific epitopes to various compartments of the immune system. Several strategies, which include vaccines composed of DNA, proteins, peptides, whole cells, carbohydrates and recombinant vectors, have been used to generate tumor vaccines. The use of recombinant vectors includes the use of live carrier vectors such as vaccinia, BCG, canarypox, and Salmonella, which are designed to stimulate the appropriate immune responses to tumors and infectious agents as a by-product of infection. Effective vaccines need to elicit strong, long-term, and multi-haplotype protection against a tenacious cancer. An ideal vaccine would satisfy these requirements and elicit an inescapable immune response by delivering a wide-variety of antigens.